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Salmonella typhimurium Suppresses Tumor Growth via the Pro-Inflammatory Cytokine Interleukin-1?.

ABSTRACT: Although strains of attenuated Salmonella typhimurium and wild-type Escherichia coli show similar tumor-targeting capacities, only S. typhimurium significantly suppresses tumor growth in mice. The aim of the present study was to examine bacteria-mediated immune responses by conducting comparative analyses of the cytokine profiles and immune cell populations within tumor tissues colonized by E. coli or attenuated Salmonellae. CT26 tumor-bearing mice were treated with two different bacterial strains: S. typhimurium defective in ppGpp synthesis (?ppGpp Salmonellae) or wild-type E. coli MG1655. Cytokine profiles and immune cell populations in tumor tissue colonized by these two bacterial strains were examined at two time points based on the pattern of tumor growth after ?ppGpp Salmonellae treatment: 1) when tumor growth was suppressed ('suppression stage') and 2) when they began to re-grow ('re-growing stage'). The levels of IL-1? and TNF-? were markedly increased in tumors colonized by ?ppGpp Salmonellae. This increase was associated with tumor regression; the levels of both IL-1? and TNF-? returned to normal level when the tumors started to re-grow. To identify the immune cells primarily responsible for Salmonellae-mediated tumor suppression, we examined the major cell types that produce IL-1? and TNF-?. We found that macrophages and dendritic cells were the main producers of TNF-? and IL-1?. Inhibiting IL-1? production in Salmonellae-treated mice restored tumor growth, whereas tumor growth was suppressed for longer by local administration of recombinant IL-1? or TNF-? in conjunction with Salmonella therapy. These findings suggested that IL-1? and TNF-? play important roles in Salmonella-mediated cancer therapy. A better understanding of host immune responses in Salmonella therapy may increase the success of a given drug, particularly when various strategies are combined with bacteriotherapy.

SUBMITTER: Kim JE

PROVIDER: S-EPMC4615736 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Salmonella typhimurium Suppresses Tumor Growth via the Pro-Inflammatory Cytokine Interleukin-1β.

Kim Jung-Eun JE Phan Thuy Xuan TX Nguyen Vu Hong VH Dinh-Vu Hong-Van HV Zheng Jin Hai JH Yun Misun M Park Sung-Gyoo SG Hong Yeongjin Y Choy Hyon E HE Szardenings Michael M Hwang Won W Park Jin-A JA Park SunHee S Im Sin-Hyeog SH Min Jung-Joon JJ

Theranostics 20151006 12

Although strains of attenuated Salmonella typhimurium and wild-type Escherichia coli show similar tumor-targeting capacities, only S. typhimurium significantly suppresses tumor growth in mice. The aim of the present study was to examine bacteria-mediated immune responses by conducting comparative analyses of the cytokine profiles and immune cell populations within tumor tissues colonized by E. coli or attenuated Salmonellae. CT26 tumor-bearing mice were treated with two different bacterial strai ...[more]

PMID: 26516371

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Project description:Engineered Salmonella typhimurium (S.t-ΔpGlux/pT-ClyA) and attenuated Salmonella typhimurium (SL: Salmonella typhimurium with a defect in the synthesis of guanine 5'-diphosphate-3'-diphosphate) exhibit similar tumor targeting capabilities (Kim et al. in Theranostics 5:1328-1342, 2015; Jiang et al. in Mol Ther 18:635-642, 2013), but S.t-ΔpGlux/pT-ClyA exerts superior tumor suppressive effects. The aim of this study was to investigate whether S.t-ΔpGlux/pT-ClyA inhibits colon cancer growth and recurrence by promoting increased IL-1β production. The CT26 tumor mouse model was used, and mice were treated in the following ways: PBS, S.t-ΔpGlux/pT-ClyA(+) + IL-1βAb, SL, S.t-ΔpGlux/pT-ClyA(-), and S.t-ΔpGlux/pT-ClyA(+). Dynamic evaluation of the efficacy of S.t-ΔpGlux/pT-ClyA in the treatment of colon cancer was assessed by MRI. Western blot, immunofluorescence and flow cytometry analysis were used to investigate IL-1β-derived cells and IL-1β expression on tumor cells and immune cells to analyze the regulatory mechanism. IL-1β levels in tumors colonized by S.t-ΔpGlux/pT-ClyA were significantly increased and maintained at high levels compared to control treatments. This increase caused tumors to subside without recurrence. We examined the immune cells mediating S.t-ΔpGlux/pT-ClyA-induced tumor suppression and examined the major cell types producing IL-1β. We found that macrophages and dendritic cells were the primary IL-1β producers. Inhibition of IL-1β in mice treated with S.t-ΔpGlux/pT-ClyA using an IL-1β antibody caused tumor growth to resume. This suggests that IL-1β plays an important role in the treatment of cancer by S.t-ΔpGlux/pT-ClyA. We found that in St-ΔpGlux/pT-ClyA-treated tumors, expression of molecules involved in signaling pathways, such as NLRP3, ASC, Caspase1, TLR4, MyD88, NF-kB and IL-1β, were upregulated, while in ΔppGpp S. typhimurium treated animals, TLR4, MyD88, NF-kB and IL-1β were upregulated with NLRP3, ASC, and Caspase1 being rarely expressed or not expressed at all. Using S.t-ΔpGlux/pT-ClyA may simultaneously activate TLR4 and NLRP3 signaling pathways, which increase IL-1β expression and enhance inhibition of colon cancer growth without tumor recurrence. This study provides a novel platform for treating colon cancer.

Dataset Information

Salmonella typhimurium Suppresses Tumor Growth via the Pro-Inflammatory Cytokine Interleukin-1?.

Publications

Salmonella typhimurium Suppresses Tumor Growth via the Pro-Inflammatory Cytokine Interleukin-1β.

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